Biomarkers to enable early diagnosis and intervention and to monitor progression

Clinical diagnosis of Alzheimer’s disease (AD) is difficult and has an error rate of 40%. Cerebrospinal fluid biomarkers -– β-amyloid 42 and 42/40, hyperphosphorylated tau, total tau, neurofilament light [NFL], neurogranin – are therefore currently used for diagnosis in research environments. These biomarkers together with new techniques to detect tau and NFL in the blood and other noninvasive techniques were discussed in relation to their ability to detect early AD and disease progression and their translatability to widespread clinical use at AAT-AD/PD.

Clinical diagnosis of AD is difficult, especially for early AD and has an error rate of 40%, said Kaj Blennow, University of Gothenburg,  Sweden. Biomarkers in cerebrospinal fluid (CSF), blood and brain are therefore increasingly used to diagnose AD in clinical trials and are now being validated to enable their general clinical use.

CSF biomarkers have high diagnostic accuracy in mild cognitive impairment

Biomarkers in the CSF AD toolbox and their associated pathology in AD include:

  • β-amyloid 42 or β-amyloid 42/40 — β-amyloid aggregation
  • hyperphosphorylated tau (P-tau) — tau hyperphosphorylation
  • total tau (T-tau) and neurofilament light (NFL) — neuronal degeneration
  • neurogranin — synaptic dysfunction

High CSF T-tau and P-tau predict progression

These CSF biomarkers have high diagnostic accuracy in the mild cognitive impairment (MCI) stage of AD, and the increase in CSF neurogranin seems to be specific for prodromal and clinical disease, said Professor Blennow. He added that high T-tau and P-tau predict progression in the MCI and preclinical phase with 87% specificity, especially when combined with low β-amyloid 42.

Blood biomarkers are the ultimate aim, said Professor Blennow. Neuronal proteins, such as tau and NFL, in blood can now be quantified using ultra-sensitive assays; and recent studies suggest that low plasma β-amyloid 42 or β-amyloid 42/40 correlates with amyloid deposition evaluated by positron emission tomography (PET).

Steps to speed up widespread clinical availability of biomarkers

Use of biomarkers to diagnose or monitor AD are currently restricted to research environments and now need validation to enable general clinical use for patients with cognitive impairment, said Giovanni Frisoni, Laboratory of Neuroimaging of Aging, University of Geneva, Switzerland.

Biomarkers are currently used only in research environments

Together with other experts, Professor Frisoni has set up a five-phase roadmap to clinical validation for AD biomarkers — starting from phase 1 showing evidence of analytical validity through clinical validity in case-control studies (phases 2 and 3) and clinical utility in the general population (phases 4 and 5).

Professor Frisoni also highlighted the AMYPAD project involving eight academic centers, three pharmaceutical companies, two small/medium-sized enterprises and one patient organization spread across Europe to determine when best to perform diagnostic β-amyloid imaging in a real-life clinical setting.

Biomarkers to detect early disease and disease progression

Simon Lovestone, Professor of Translational Medicine, University of Oxford, Oxford, UK described a pilot study for the Deep and Frequent Phenotyping study to identify biomarkers to enable early detection of AD. The study led by the University of Oxford is funded by a coalition of pharmaceutical companies and involves researchers from eight UK universities and the Alzheimer’s Society.

In a pilot study of 20 participants with mild AD, the tau tracer AV1451 but not the amyloid tracer AV45 correlate well with CSF tau/β-amyloid ratio, while both CSF and PET measures of tau pathology correlated with cognitive change over 6 months.

Cortical amyloid correlated with entorhinal tau measures using PET, but a strong negative correlation was observed between PET tau measures and age.

This pilot study suggests that both tau and β-amyloid pathologies are involved in AD pathogenesis and that tau is a driver of progression, especially in younger people, said Professor Lovestone.

Brain tau and myoinositol/creatine concentration may be markers of progression

Olga Voevodskaya, Karolinska Institute, Stockholm, Sweden described a small study to assess longitudinal change in brain myoinositol levels in early AD using noninvasive proton magnetic spectroscopy. Myoinositol/creatine concentration increased over time in participants who were β-amyloid-positive at baseline and did not change significantly in those who were negative. Carriers of ApoE-e4 had higher rates of myoinositol/creatine increase (3.9%/year).

The Alzheimer's Disease Neuroimaging Initiative enables global collaboration

The goal of the Alzheimer's Disease Neuroimaging Initiative (ADNI) is to standardize and validate magnetic resonance and PET imaging and blood/CSF biomarkers for AD treatment trials, said Michael Weiner, Principle Investigator of ADNI, University of California San Francisco, San Francisco, USA.

ADNI is a global resource to accelerate clinical trials

ADNI is a global, multisite, longitudinal, observational study founded in 2004, two-thirds funded by the National Institute on Aging and one-third funded by industry that has established standardized methods for imaging and biomarker collection and analysis. It enables scientists worldwide to conduct cohesive research and share all data through a secure research data repository, the LONI Image & Data Archive (https://ida.loni.usc.edu/).

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